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    TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

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    Authors
    Moukengue, B
    Brown, HK
    Charrier, C
    Battaglia, S
    Baud'huin, M
    Quillard, T
    Pham, TM
    Pateras, IS
    Gorgoulis, Vassilis G
    Helleday, T
    Heymann, D
    Berglund, UW
    Ory, B
    Lamoureux, F
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    Affiliation
    Universite de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifies, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France
    Issue Date
    2020
    
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    Abstract
    BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. METHODS: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. FINDINGS: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. INTERPRETATION: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. FUNDING: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.
    Citation
    Moukengue B, Brown HK, Charrier C, Battaglia S, Baud'huin M, Quillard T, et al. TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model. EBioMedicine. 2020;53:102704.
    Journal
    EBioMedicine
    URI
    http://hdl.handle.net/10541/622876
    DOI
    10.1016/j.ebiom.2020.102704
    PubMed ID
    32151797
    Additional Links
    https://dx.doi.org/10.1016/j.ebiom.2020.102704
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ebiom.2020.102704
    Scopus Count
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    All Paterson Institute for Cancer Research

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